Neurofibromatosis type 1 (NF1) is a common (approximately 100,000 Americans) genetic disorder of dysregulated cell growth. Affected people can develop multiple (tens, hundreds, or thousands) of soft fleshy tumors called neurofibromas. People with NF1 also develop malignant cancers. There are limited therapies and no cures for NF1. At this time it is essentially impossible to predict the severity of the disorder. With few exceptions, neither mutation testing of the involved gene (NF1) nor the severity of other affected family members help in estimating the clinical course of the condition. In this study we study the wide variability in severity seen in families with NF1. In our translational approach in the protocol Variation in Gene Expression in Neurofibromatosis Type 1 we quantitatively evaluate families with NF1 using a variety of methods (physical exam, magnetic resonance imaging (MRI), skin and eye photography, echocardiography, dental evaluation). We plan to correlate differences in these measurements with differences in the expression of genes, as determined by a microarray. The ultimate goal is to identify genes associated with severity. Differences in these genes (such as single nucleotide polymorphisms (SNPs)) may be useful in predicting the severity of the disorder. Gene products associated with severity may also be useful therapeutic targets.[unreadable] [unreadable] Dr. Stewart joined NHGRI at the end of November 2004. The IRB approved our project in April 2005 and recruitment started shortly thereafter. By the end of fiscal 2008, we had phenotyped approximately 100 individuals affected with NF1 and collected DNA from nearly all their parents. As a pilot project, we cultured 25 lymphoblastoid cell lines (LCLs) from this phenotyped group of individuals affected with NF1, harvested RNA and hybridized it to microarrays (expression profiling). We then examined the correlation between a variety of phenotypes (height, number of caf-au-lait spots, tumor burden, etc) and each of the approximately 24,000 genes expressed on the array. We identified a gene whose level appears to influence height in individuals with NF1. We then expanded the investigation and cultured LCLs from approximately 75 individuals with NF1 and approximately 25 controls. We are currently investigating the correlation of expression profiles of these 100 subjects with phenotype data. Our goal is to 1) validate the gene identified in the pilot study as a modifier gene (for height in NF1) and 2) identify other putative modifier genes. [unreadable] [unreadable] We have also developed a collaborative project (using funds from the Bench-to-Bedside program) with Dr. Brigitte Widemann and Dr. Thomas Hornyak of the National Cancer Institute to investigate the growth and biology of neurofibromas. The project, titled Natural history and biology of dermal neurofibromas in neurofibromatosis type 1 was approved by the NHGRI IRB in May 2006. It is designed to investigate the growth rate and rate of appearance of dermal neurofibromas using several imaging modalities. We will also biopsy a dermal neurofibroma and normal skin. To streamline recruiting, the eligibility criteria overlap with that of our primary project, Variation in Gene Expression in Neurofibromatosis Type 1. By the end of fiscal 2008, we were evaluating, longitudinally, the dermal neurofibromas from 12 individuals affected with NF1.[unreadable] [unreadable] Since Dr. Stewart is trained as an internist, he has a special interest in manifestations of NF1 affecting adults. To this end, we have been evaluating individuals with NF1 with unique and under-recognized disease features in the adult. By the end of fiscal 2008 we had resected glomus tumors from four individuals with NF1, which are uncommon but painful benign tumors in the fingertips. We have made significant progress in understanding the molecular mechanism of the development of the tumors and are preparing a manuscript detailing our findings. Another manuscript investigating Lisch nodules in adults with NF1 is also in preparation.[unreadable] [unreadable] In fiscal 2008, we published in the American Journal of Medical Genetics an invited review on the 9q subtelomere deletion syndrome, an uncommon chromosomal disorder Dr. Stewart described as a genetics fellow at another institution. We presented our findings at the 2007 annual meeting of the American Society of Human Genetics, 2008 annual meeting of the American College of Medical Genetics and the 2008 annual meeting of the Childrens Tumor Foundation.